A Healthy Volunteer Study of Safety, Tolerability & PK of Co-administered Single Doses of OZ439 and Mefloquine

This study has been terminated.
(Decision taken to halt progression of mefloquine as a potential partner for OZ439 as a single dose cure due to low probability of success)
Sponsor:
Collaborator:
University of Cape Town
Information provided by (Responsible Party):
Medicines for Malaria Venture
ClinicalTrials.gov Identifier:
NCT01615822
First received: June 7, 2012
Last updated: July 18, 2013
Last verified: July 2013
  Purpose

OZ439 is a novel, synthetic trioxolane medicine which is related to artemisinin, but has the advantage of a longer elimination half-life so is being developed to be administered together with a potential partner drug e.g. mefloquine as a single dose cure for uncomplicated malaria. The study findings will be used to inform the dose and design of future studies. The aim of the study is to establish the safety, tolerability and pharmacokinetics of co-administered OZ439 and MQ at a range of doses up to the maximum tolerated dose, in healthy volunteers.


Condition Intervention Phase
Malaria
Drug: OZ439 100mg
Drug: OZ439 y mg
Drug: OZ439 z mg, single dose
Drug: MQ 250 mg, single dose
Drug: MQ a mg, single dose
Drug: MQ b mg, single dose
Drug: placebo to OZ439
Drug: placebo to MQ
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase I Healthy Volunteer Study Investigating the Safety, Tolerability & Pharmacokinetics of Co-administered Single Doses of OZ439 and Mefloquine

Resource links provided by NLM:


Further study details as provided by Medicines for Malaria Venture:

Primary Outcome Measures:
  • Area under the plasma concentration versus time curve (AUC) of OZ439 [ Time Frame: Up to 42 days post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.



Secondary Outcome Measures:
  • Peak Plasma Concentration (Cmax) of OZ439 [ Time Frame: Up to 42 days post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.


  • Tmax (the time to reach Cmax after drug ingestion) for OZ439 [ Time Frame: Up to 42 days post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.


  • T½ (half-life) of OZ439 [ Time Frame: Up to 42 days post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.


  • Area under the plasma concentration versus time curve (AUC) of MQ [ Time Frame: Up to 42 days post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.


  • Peak Plasma Concentration (Cmax) of MQ [ Time Frame: Up to 42 days post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.


  • Tmax (the time to reach Cmax after drug ingestion) for MQ [ Time Frame: Day 42 post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.


  • T½ (half-life) of MQ [ Time Frame: Day 42 post-dose ] [ Designated as safety issue: No ]

    Period 1 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h and 96h post-dose.

    Period 2 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.

    Period 3 Predose (-0.5h to 0h), 1h, 2h, 3h, 4h, 6h, 8h, 10h, 16h, 24h, 36h, 48h, 72h, 96h, 168h, 240h, 336h, Day 28, Day 35 and Day 42 post-dose.



Enrollment: 24
Study Start Date: August 2012
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: OZ439 single dose Drug: OZ439 100mg
OZ439 100mg oral suspension, single dose
Drug: OZ439 y mg
OZ439 y mg oral suspension, single dose
Drug: OZ439 z mg, single dose
OZ439 z mg oral suspension single dose. Dose to be determined based on PK data for previous cohort.
Placebo Comparator: placebo to OZ439 single dose Drug: placebo to OZ439
Placebo to OZ439 oral suspension single dose.
Experimental: OZ439 plus MQ single doses Drug: OZ439 y mg
OZ439 y mg oral suspension, single dose
Drug: OZ439 z mg, single dose
OZ439 z mg oral suspension single dose. Dose to be determined based on PK data for previous cohort.
Drug: MQ 250 mg, single dose
Mefloquine 250 mg tablet, single dose
Drug: MQ a mg, single dose
Mefloquine b mg oral tablet, single dose. Dose to be determined based on PK data for previous cohort.
Drug: MQ b mg, single dose
Mefloquine b mg tablet single dose. Dose to be determined based on PK data for previous cohort.
Experimental: OZ439 plus MQ placebo single doses Drug: placebo to MQ
placebo to Mefloquine tablet, single dose
Experimental: OZ439 placebo plus MQ single doses Drug: MQ 250 mg, single dose
Mefloquine 250 mg tablet, single dose
Drug: MQ a mg, single dose
Mefloquine b mg oral tablet, single dose. Dose to be determined based on PK data for previous cohort.
Drug: MQ b mg, single dose
Mefloquine b mg tablet single dose. Dose to be determined based on PK data for previous cohort.
Drug: placebo to OZ439
Placebo to OZ439 oral suspension single dose.
Placebo Comparator: OZ439 placebo & MQ placebo single doses Drug: placebo to OZ439
Placebo to OZ439 oral suspension single dose.
Drug: placebo to MQ
placebo to Mefloquine tablet, single dose
Experimental: MQ single dose Drug: MQ b mg, single dose
Mefloquine b mg tablet single dose. Dose to be determined based on PK data for previous cohort.
Placebo Comparator: MQ placebo sd Drug: placebo to MQ
placebo to Mefloquine tablet, single dose

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Written informed consent prior to any study procedures
  • Healthy male and non-childbearing potential female volunteers of between 18 and 55 years of age, as determined by pre-study medical history, physical examination (including body temperature and a 12-lead ECG). Subjects must have no history of cardiovascular disease or conduction abnormality
  • Female volunteers must have a negative serum pregnancy test at screening
  • Females must be of non-childbearing potential, i.e. surgically sterilized, or post-menopausal (amenorrhea for at least 1 year and confirmed by follicle stimulating hormone [FSH] levels)
  • Male volunteers and their partner(s) must agree to use a double barrier method of contraception including condom plus diaphragm/IUD/stable oral/transdermal/injectable hormonal contraceptive by female partner for at least 14 days prior to first dose of study drug through 90 days after the last dose. Abstinent volunteers agree starting a double barrier method if they start sexual relationships during the study and up to 90 days after the last dose of either study drug
  • Body mass Index between 18 and 30kg/m2, inclusive; and a total body weight >50 kg
  • Laboratory tests at screening within normal ranges or if outside the normal range not clinically significant as judged by the Investigator and confirmed and agreed by the sponsor. For Liver Function Tests, AST, ALT or conjugated bilirubin must be <1.5xULN for the subject to be included.

Exclusion Criteria:

  • A diagnosis of Plasmodium falciparum, vivax, ovale, malariae, or knowlesi malaria, confirmed by a malaria rapid diagnostic antigen test and/ or thick blood smear
  • General:
  • Received an investigational drug or participated in another research study within 30 days of the first dose of study drug or at any time through the study
  • Evidence of current or history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, haematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, or clinically significant current infection.
  • Pharmacokinetic:
  • Evidence of current or history of clinically significant gastrointestinal (excluding appendectomy, cholecystectomy) disease
  • Any condition that could possibly affect drug absorption, such as gastrectomy, diarrhea and lactose intolerance
  • Use of any medications, vitamins, herbal supplements, dietary supplements or vaccinations within 14 days of the first dose of study drug or at any time through the study, unless prior approval is granted. This includes any drugs that are substrates, inhibitors or inducers of CYP3A4. Intermittent use of acetaminophen at doses of up to 2g/day is permitted
  • History of drug or alcohol abuse within 2 years of Screening
  • History of alcohol consumption within 24 hours of any study visit, or consumption of >2 units alcohol in any one day or consumption of >15 units alcohol in any one week throughout the study
  • Tobacco users (includes stopping smoking up to 90 days prior to the screening evaluation). Tobacco use includes smoking and use of snuff and nicotine containing products
  • Consumption of fruit juices within 7 days prior to dosing with study drug
  • Participation in unaccustomed strenuous exercise within 7 days prior to
  • Screening or within 7 days prior to dosing of the study drug.
  • Positive urine drug screen (cocaine, amphetamine, opioids, cannabis, benzodiazepine) at Screening
  • Positive test for HIV-1, HBsAg or HCV
  • Contraindication to the study drugs
  • Known hypersensitivity to MQ or artemisinins
  • QTc greater than 450msec as corrected by the Fridericia's formula
  • Any personal or family history of suicidal behavior or suicidality or depression, psychosis, anxiety disorder, schizophrenia, or other major psychiatric disorder
  • History of seizures
  • Suicidal behavior or any suicidal ideation using Columbia Suicide Severity rating Scale
  • Current low mood or behaviour changes, anxiety, depression, feelings of persecution, crying, aggression, forgetfulness, agitation, confusion or hallucinations (using QIDS)
  • Current parasomnia based on ICSD criteria and screening by interview.
  • Includes confusional arousals, sleepwalking, sleep terrors, nightmares, sleep paralysis, sleep related hallucinations and dream enactment (REM behavioural disorder)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01615822

Locations
South Africa
Division of Clinical Pharmacology, University of Cape Town
Cape Town, South Africa, 7925
Sponsors and Collaborators
Medicines for Malaria Venture
University of Cape Town
Investigators
Principal Investigator: Karen I Barnes University of Cape Town
  More Information

No publications provided

Responsible Party: Medicines for Malaria Venture
ClinicalTrials.gov Identifier: NCT01615822     History of Changes
Other Study ID Numbers: MMV_OZ439_12_001
Study First Received: June 7, 2012
Last Updated: July 18, 2013
Health Authority: South Africa: Medicines Control Council

Keywords provided by Medicines for Malaria Venture:
Malaria
PK
OZ439
Mefloquine
Healthy Volunteers

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Mefloquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 28, 2014